1. Field of the Invention
The present invention relates to transition metal catalysts for aromatic or vinylic Cxe2x80x94O, Cxe2x80x94N, and Cxe2x80x94C bond formation, and more particularly to transition metal catalysts for aromatic or vinylic Cxe2x80x94O, Cxe2x80x94N, and Cxe2x80x94C bond formation that include ferrocenyl ligands and a transition metal atom such as platinum, palladium, or nickel. The present invention also relates to method of forming compounds containing aromatic Cxe2x80x94O, Cxe2x80x94N, and Cxe2x80x94C bonds using the transition metal catalysts.
2. Brief Description of the Related Art
Mild, aromatic or vinylic substitution to form Cxe2x80x94O, Cxe2x80x94N, and Cxe2x80x94C bonds is a difficult transformation. For reactions of unactivated aryl halides, direct, uncatalyzed substitutions and copper-mediated couplings typically require temperatures of 100xc2x0 C. or greater (Bacon, R. G. R.; Rennison, S. C. J. Chem. Soc. (C) 1969, 312-315; Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Amn. Chem. Soc. 1997, 119, 10539-10540; Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986-2987).
Alternative approaches have suffered similar drawbacks and disadvantages. For example, diazotization and displacement with oxygen or nitrogen nucleophiles is generally limited in scope and uses stoichiometric amounts of copper in its mildest form (March, J. In Advanced Organic Chemistry John Wiley and Sons: New York, 1985; pp 601). Recently, palladium catalysts for the formation of diaryl and alkyl aryl ethers from unactivated aryl halides have been shown to be useful in these reactions (Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224-3225). However, this system for Cxe2x80x94O bond-formation as well as similar systems (Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378) required temperatures similar to those for copper-mediated processes (Bacon, R. G. R.; Rennison, S. C. J. Chem. Soc. (C) 1969, 312-315; Marcoux, J. F.; Doye,. S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539-10540; Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986-2987; Boger, D. L.; Yohannes, D. J. Org. Chem. 1991, 56, 1763; Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043-5051). In addition, several catalysts have been shown to induce aromatic Cxe2x80x94N bond-formation from aryl halides and sulfonates. Yet, the termperatures, for general reactions remain high in many cases, and the selectivities for formation of the desired aniline derivative instead of the undesired arene or diarylamine are often lower than optimal for synthetic applications.(Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1444; Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158; Huang, J.; Grassa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307; Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575; Stauffer, S. I.; Hauck, S. I.; Lee, S.; Stambuli, J.; Hartwig, J. F. Org. Lett. 2000, 2, 1423) Finally, catalysts have been developed for aromatic or vinylic Cxe2x80x94C bond formation, but again the conditions for these reactions are often harsh.(Suzuki, A. J. Organomet. Chem. 1999, 576, 147; Buchwals, S. L.; Fox, J. M. The Strem Chemiker, 2000, 18, 1; Zhang, C; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804; Beletskaya, I. P. Cheprakov, A. V. Chem. Rev. 2000, 100, 3009; Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123) In particular for each of these three classes of reactions, the bond-forming processes are especially difficult to conduct under mild conditions with high selectivity when using chloroarenes.
Unfortunately, reaction conditions such as those described above are quite harsh and require special equipment and techniques to accomplish even small scale syntheses. In addition, larger scale reactions of these reactions, such as those used in large-scale pharmaceutical manufacturing, are generally impractical and expensive due to these extreme reaction conditions. What is needed in the art is a catalytic method of aromatic or vinylic carbon-oxygen, carbon-nitrogen, and carbon-carbon bond formation that occurs under mild conditions (e.g., room temperature and atmospheric pressure) and that is easily scalable for large-scale synthesis, for example, in the pharmaceutical industry. The present invention is believed to be an answer to that need.
In one aspect, the present invention is directed to a transition metal catalyst, comprising a Group 8 metal and a ligand having the structure 
wherein R, Rxe2x80x2 and Rxe2x80x3 are organic groups having 1-15 carbon atoms, n=1-5, and m=0-4.
In another aspect, the present invention is directed to a method of forming a compound having an aromatic or vinylic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond, comprising the step of reacting a first substrate and a second substrate in the presence of a transition metal catalyst, wherein the first substrate comprises an aryl halide reagent or an aryl sufonate reagent, and the second substrate comprises an alcohol reagent, an alkoxide reagent, a silanol reagent, a siloxide reagent, an amine reagent, an organoboron reagent, an organozinc reagent, an organomagnesium reagent, a malonate reagent, a cyanoacetate reagent, or an olefinic reagent, and wherein the transition metal catalyst comprises a Group 8 metal and a ligand having the structure 
wherein R and Rxe2x80x2 are organic groups having 1-15 carbon atoms, and n=1-5; under reaction conditions effective to form the compound, wherein the compound has an aromatic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond between the first substrate and the second substrate.
In yet another aspect, the present invention is directed to a method of forming a compound having an aromatic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond, comprising the step of reacting a first substrate and a second substrate in the presence of a transition metal catalyst, wherein the first substrate comprises a selected aryl halide reagent or an aryl sufonate reagent and the second substrate is selected from the group consisting of NaOxe2x80x94C6H4xe2x80x94OMe, NaO-tBu, NaOxe2x80x94Si-(tBu)Me2, HOxe2x80x94C6H4xe2x80x94OMe, HO-tBu, HOxe2x80x94Si-(tBu)Me2, primary amines, secondary amines, alkyl amines, benzylic amines, aryl amines including morpholine, dibutylamine, aniline, n-butylamine, n-hexylamine, methylaniline, aminotoluene; organoboron reagents, organozinc reagents, organomagnesium reagents, indoles, ethyl cyanoacetate, diethyl malonate, methyl acrylate, and combinations thereof, and wherein the transition metal catalyst comprises a Group 8 metal selected from the group consisting of palladium, platinum, and nickel, and a ligand having the structure 
in a solvent selected from the group consisting of aromatic hydrocarbons, chlorinated aromatic hydrocarbons, ethers, water, aliphatic alcohols, and combinations thereof, under reaction conditions effective to form the compound, wherein the compound has an aromatic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond between the first substrate and the second substrate.
These and other aspects will become apparent upon reading the following detailed description of the invention.
It now has been surprisingly found, in accordance with the present invention, that a solution is provided to the problem of providing a general and efficient catalytic method of aromatic or vinylic carbon-oxygen, carbon-nitrogen, and carbon-carbon bond formation between two substrates that occurs under mild conditions (e.g., room temperature and atmospheric pressure). The present inventors have solved this problem by utilizing a catalyst that includes a transition metal catalyst comprising a Group 8 metal and a substituted ferrocenylphosphineligand. The catalyst is useful in a general and efficient process of formation of reaction products containing an aromatic carbon-oxygen, carbon-carbon, or carbon-nitrogen bond. Production of carbon-oxygen, carbon-carbon, or carbon-nitrogen bonds between substrates under mild conditions is particularly advantageous in the pharmaceutical industry where active starting substrates can be rapidly degraded by harsh chemical coupling conditions. The aromatic carbon-oxygen, carbon-carbon, or carbon-nitrogen bonds are formed under mild conditions and in the presence of the catalyst using a variety of starting substrates, most notably aryl halide reagents, aryl sulfonate reagents, alkoxide reagents, siloxide reagents, alcohol reagents, silanol reagents, amine reagents, organoboron reagents, organomagnesium reagents, organozinc reagents, malonate reagents, cyanoacetate reagents, and olefinic reagents. In addition to forming an aromatic carbon-oxygen bond between two distinct substrates, the catalyst and method of the present invention is also useful in intramolecular reactions, such as intramolecular etherification, amination, or vinylation where a single compound comprises each of the two substrates.
As defined herein, the term xe2x80x9csubstratexe2x80x9d includes distinct compounds possessing the above reactive groups (for example, aryl halides, aryl sulfonates, alkoxides, alcohols, siloxides, silanols, amines or related compounds with an Nxe2x80x94H bond, organoborons, organomagnesiums, organozincs, malonates, cyanoesters, and olefinic compounds) as well as a single compound that includes reactive groups such as aryl halides, aryl sulfonates, alkoxides, alcohols, siloxides, silandls, amines or related compounds with an Nxe2x80x94H bond, organoboron, organomagnesium, organozinc, malonate, cyanoester, and olefinic groups, such that an intramolecular reaction can take place in the presence of the catalyst of the present invention. As defined herein, the term xe2x80x9caromaticxe2x80x9d refers to a compound whose molecules have the ring structure characteristic of benzene, naphthalene, phenanthroline, anthracene, related heterocycles such as pyridines, pyrimidines, thiophenes, furans, pyrroles, and the like. The phrase xe2x80x9caromatic carbon-oxygen, carbon-nitrogen, or carbon-carbon bondxe2x80x9d refers to a covalent bond between a carbon atom of an aromatic or heteroaromatic ring of a first substrate, and an oxygen, nitrogen, or carbon atom of a second substrate. The terms xe2x80x9caminexe2x80x9d and xe2x80x9camine reagentxe2x80x9d are broadly defined herein to encompass primary amines, secondary amines, alkyl amines, benzylic amines, aryl amines, as well as related compounds with Nxe2x80x94H bonds, including carbamates and cyclic or heterocyclic amine compounds.
As indicated above, the transition metal catalyst of the present invention includes a transition metal atom complexed with a ferrocenyl ligand. In one embodiment, the ferrocenyl ligand portion of the catalyst is represented by the formula: 
wherein R, Rxe2x80x2, and Rxe2x80x3 are organic groups having 1-15 carbon atoms, n=1-5, and m=0-4. Within the ferrocenyl ligand, R can be any organic group possessing 1-15 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-5 carbon atoms. In one preferred embodiment, R possesses 4 carbon atoms, and is a tertiary butyl group (tBu). Rxe2x80x2 can also be any organic group possessing 1-15 carbon atoms, with or without additional substitutents such as halides, and the like. More preferably, Rxe2x80x2 possesses 1-10 carbon atoms, and most preferably 2-8 carbon atoms. In one embodiment, Rxe2x80x2 may be phenyl, MeOxe2x80x94C6H4, F3Cxe2x80x94C6H4, methyl, or o-tolyl. In addition, the number of Rxe2x80x2 groups preferably ranges from 1-5, most preferably either 4 or 5. Rxe2x80x3 can also be any organic group possessing 1-15 carbon atoms. Preferable substituents for Rxe2x80x3 include methyl, ethyl, propyl, aminoalkyl, 1-dialkylaminoethyl, 1-alkoxyethyl, phenyl, methoxyphenyl, halophenyl, naphthyl, and the like. The number of Rxe2x80x3 groups ranges from 0-4.
In one preferred embodiment, the transition metal catalyst is a palladium complex with a ferrocenyl ligand having the formula: 
wherein Rxe2x80x2 is phenyl, MeOxe2x80x94C6H4, F3Cxe2x80x94C6H4, methyl, or o-tolyl, R is tert-butyl, and n is 4 or 5.
In one particularly preferred embodiment, the transition metal catalyst is a palladium complex with a ferrocenyl ligand having the formula: 
The transition metal atom or ion is required to be a Group 8 transition metal, that is, a metal selected from iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, and platinum. More preferably, the Group 8 metal is palladium, platinum, or nickel, and most preferably, palladium. The Group 8 metal may exist in any oxidation state ranging from the zero-valent state to any higher variance available to the metal. The catalyst may be formed from a mixture of P(C5H4FeC5H5)(t-Bu)2, Pd(OAc)2, NaO-t-Bu and PhCl according to Equation 1. 
In the presence of a Group 8 metal, such as iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, or platinum, the ferrocenyl ligand is formed into an active catalyst that is useful in catalyzing reactions that form carbon-oxygen, carbon-nitrogen, or carbon-carbon bonds between the substrates.
The transition metal catalyst may be synthesized first and thereafter employed in the reaction process. Alternatively, the catalyst can be prepared in situ in the reaction mixture. If the latter mixture is employed, then a Group 8 catalyst precursor compound and the ferrocenyl ligand are independently added to the reaction mixture wherein formation of the transition metal catalyst occurs in situ. Suitable precursor compounds include alkene and diene complexes of the Group 8 metals, preferably, di(benzylidene)acetone (dba) complexes of the Group 8 metals, as well as, monodentate phosphine complexes of the Group 8 metals, and Group 8 carboxylates or halides. In the presence of the ferrocenyl ligand, in situ formation of the transition metal catalyst occurs. Non-limiting examples of suitable precursor compounds include [bis-di(benzylidene)acetone]palladium (0) as shown in Eq. 1, tetrakis-(triphenylphosphine)-palladium (0), tris-[di(benzylidene)acetone]palladium (0), tris-[di(benzylidene)acetone]-dipalladium (0), palladium acetate, palladium chloride, and the analogous complexes of iron, cobalt, nickel, ruthenium, rhodium, osmium, iridium, and platinum.
Any of the aforementioned catalyst precursors may include a solvent of crystallization. Group 8 metals supported on carbon, preferably, palladium on carbon, can also be suitably employed as a precursor compound. Preferably, the catalyst precursor compound is bis-[di(benzylidene)acetone]palladium(0).
As indicated above, the present invention is also directed to a method of forming a compound having an aromatic carbon-oxygen, carbon-carbon, or carbon-nitrogen bond, comprising the step of reacting a first substrate and a second substrate in the presence of the transition metal catalyst described above. Each of these steps and components are described in more detail below.
Aryl halides that are useful as reagents include any compounds in which a halide atom is covalently bound to an aryl ring structure, such as a benzene ring or a heteroaromatic ring. Nonlimiting examples of suitable aryl halide reagents include bromobenzene, chlorobenzene, methoxy bromo- or chlorobenzene, bromo- or chloro toluene, bromo- or chloro benzophenone, bromo- or chloro nitrobenzene, halopyridines, halopyrazines, halopyrimidines, and the like. The structures of several examples of useful aryl halides are shown in Table A below:
In each of the structures shown in Table A, X may be any halogen, for example, bromine, chlorine, flourine, or iodine. Additionally, X may be a sulfonate group, such that aryl sulfonates may also be used in the method of the present invention.
As indicated above, the second substrate may be an alcohol reagent, an alkoxide reagent, a silanol reagent, a siloxide reagent, an amine reagent, an organoboron reagent, an organozinc reagent, an organomagnesium reagent such as a Grignard reagent, a malonate reagent, a cyanoacetate reagent, an olefinic reagent, or combinations of these. Nonlimiting examples of useful alkoxide reagents include NaOxe2x80x94C6H4xe2x80x94OMe and NaO-tBu. Nonlimiting examples of useful siloxide reagents include NaOxe2x80x94Si-(tBu)Me2. Nonlimiting examples of amine reagents include compounds with Nxe2x80x94H bonds, including carbamates and cyclic or heterocyclic amine compounds such as pyrrole, indole, and the like. Examples of amine and related Nxe2x80x94H reagents that are useful in the method of the present invention include, but are not limited to, morpholine, dibutylamine, aniline, n-butylamine, n-hexylamine, methylaniline, aminotoluene, t-butylcarbamate, indole, benzophenone hydrazone and benzophenone imine.
Useful organoboron reagents include arylboronic acids, such as o-tolylboronic acid, phenylboronic acid, p-trifluoromethylphenylboronic acid, p-methoxyphenylboronic acid, o-methoxyphenylboronic acid, 4-chlorophenylboronic acid, 4-formylphenylboronic acid, 2-methylphenylboronic acid, 4-methoxyphenylboronic acid, 1-naphthylboronic acid, and the like. Useful organozinc reagents include n-butylzinc chloride, secbutylzinc chloride and phenylzinc chloride. Useful organomagnesium reagents include butylmagnesium bromide and phenylmagnesium chloride. Useful olefinic reagents include vinylarenes such as styrene and acrylic acid derivatives such as n-butyl acrylate and methyl acrylate. All of these reagents may be used as the limiting substrate or in excess quantities and are preferably used in quantities of 0.2-5 equivalents relative to the aromatic halide or sulfonate.
The method of the present invention optionally takes place in the presence of a base. Any base may be used so long as the process of the invention proceeds to the product. Non-limiting examples of suitable bases include alkali metal hydroxides, such as sodium and potassium hydroxides; alkali metal alkoxides, such as sodium t-butoxide; metal carbonates, such as potassium carbonate, cesium carbonate, and magnesium carbonate; phosphates such as trisodium or tripotassium phosphate; alkali metal aryl oxides, such as potassium phenoxide; alkali metal amides, such as lithium amide; tertiary amines, such as triethylamine and tributylamine; (hydrocarbyl)ammonium hydroxides, such as benzyltrimethylammonium hydroxide and tetraethylammonium hydroxide; and diaza organic bases, such as 1,8-diazabicyclo[5.4.0]-undec-7-ene and 1,8-diazabicyclo-[2.2.2.]-octane, and organic or alkali metal fluorides such as tetrabutylamonium fluoride or potassium fluoride. Preferably, the base is an alkali hydroxide, alkali alkoxide, alkali carbonate, alkali phosphate or alkali fluoride, more preferably, an alkali alkoxide, and most preferably, an alkali metal C1-10 alkoxide.
The quantity of base which may be used can be any quantity which allows for the formation of the product. Preferably, the molar ratio of base to arylating compound ranges from about 1:1 to about 5:1, and more preferably between about 1:1 and 3:1.
As an alternative embodiment of this invention, the catalyst may be anchored or supported on a catalyst support, including a refractory oxide, such as silica, alumina, titania, or magnesia; or an aluminosilicate clay, or molecular sieve or zeolite; or an organic polymeric resin.
The quantity of transition metal catalyst which is employed in the method of this invention is any quantity which promotes the formation of the desired product. Generally, the quantity is a catalytic amount, which means that the catalyst is used in an amount which is less than stoichiometric relative to either of the substrates. Typically, the transition metal catalyst ranges from about 0.01 to about 20 mole percent, based on the number of moles of either the first substrate or the second substrate used in the reaction. Preferably, the quantity of transition metal catalyst ranges from about 0.01 to about 2 mole percent, and more preferably from about 0.1 to about 2 mole percent, based on the moles of either substrate. In addition, the ratio of ferrocenyl ligand to Group 8 metal is preferably in the range from about 3:1 to about 0.25:1, more preferably from about 0.5:1 to about 2:1, and most preferably from about 0.8:1 to about 3:1.
The method described herein may be conducted in any conventional reactor designed for catalytic processes. Continuous, semi-continuous, and batch reactors can be employed. If the catalyst is substantially dissolved in the reaction mixture as in homogeneous processes, then batch reactors, including stirred tank and pressurized autoclaves, can be employed. If the catalyst is anchored to a support and is substantially in a heterogeneous phase, then fixed-bed and fluidized bed reactors can be used. In the typical practice of this invention, the substrates, the catalyst, and any optional base are mixed in batch, optionally with a solvent, and the resulting mixture is maintained at a temperature and pressure effective to prepare the aromatic product containing a Cxe2x80x94O, Cxe2x80x94C, or Cxe2x80x94N covalent bond.
Any solvent can be used in the process of the invention provided that it does not interfere with the formation of the product. Both aprotic and protic solvents and combinations thereof are acceptable. Suitable aprotic solvents include, but are not limited to, aromatic hydrocarbons, such as toluene and xylene, chlorinated aromatic hydrocarbons, such as dichlorobenzene, and ethers, such as dimethoxyethane, tetrahydrofuran or dioxane. Suitable protic solvents include, but are not limited to, water and aliphatic alcohols, such as ethanol, isopropanol, and cyclohexonol, as well as glycols and other polyols. The amount of solvent which is employed may be any amount, preferably an amount sufficient to solubilize, at least in part, the reactants and base. A suitable quantity of solvent typically ranges from about 1 to about 100 grams solvent per gram reactants. Other quantities of solvent may also be suitable, as determined by the specific process conditions and by the skilled artisan.
Generally, the reagents may be mixed together or added to a solvent in any order. Air is preferably removed from the reaction vessel during the course of the reaction, however this step is not always necessary. If it is desirable or necessary to remove air, the solvent and reaction mixture can be sparged with a non-reactive gas, such as nitrogen, helium, or argon, or the reaction may be conducted under anaerobic conditions. The process conditions can be any operable conditions which yield the desired product. Beneficially, the reaction conditions for this process are mild. For example, a preferred temperature for the process of the present invention ranges from about ambient, taken as about 22xc2x0 C., to about 150xc2x0 C., and preferably, from about 25xc2x0 C. to about 70xc2x0 C. The process may be run at subatmospheric pressures if necessary, but typically proceeds sufficiently well at about atmospheric pressure. The process is generally run for a time sufficient to convert as much of the substrates to product as possible. Typical reaction times range from about 30 minutes to about 24 hours, but longer times may be used if necessary.
The product can be recovered by conventional methods known to those skilled in the art, including, for example, distillation, crystallization, sublimation, and gel chromatography. The yield of product will vary depending upon the specific catalyst, reagents, and process conditions used. For the purposes of this invention, xe2x80x9cyieldxe2x80x9d is defined as the mole percentage of product recovered, based on the number of moles of starting reactants employed. Typically, the yield of product is greater than about 25 mole percent. Preferably, the yield of product is greater than about 60 mole percent, and more preferably, greater than about 75 mole percent.